Animal feed for obtaining increased production in animals

ABSTRACT

AN ANIMAL FEED COMPRISING A COMPOUND OF THE GROUP CONSISTING OF 2,4-DIHYDRO-6-PHENYL-1H-S-TRIAZOLO(4,3-A) (1,4)BENZODIAZEPIN-1-ONES OF THE FORMULA;:   2-R5,4-R4,6-(R3-PHENYL),1-(O=)-1,2-DIHYDRO-4H-S-TRIAZOLO   (4,3-A)(1,4)BENZODIAZEPINE   WHEREIN R1, R2, AND R3 ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL OF 1 TO 3 CARBON ATOMS, INCLUSIVE, HALOGEN, NITRO, CYANO, TRIFLUOROMETHYL, AND ALKOXY, ALKYLTHIO, ALKYLSULFINYL, ALKYLSUFONYL, ALKANOYLAMINO AND DIALKYLAMINO, IN WHICH THE CARBON CHAIN MOIETIES ARE OF 1 TO 3 CARBON ATOMS, INCLUSIVE, AND WHEREIN R4 AND R5 ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND ALKYL AS DEFINED ABOVE AND INCLUDING THE PHARMACOLOGICALLY ACCEPTABLE ACID ADDITON SALTS AND N-5 OXIDE INC COMBINATION WITH A NUTRIENT FEED. A PROCESS FOR OBTAINING INCREASED PRODUCTIVITY IN MEAT-PRODUCING, MILK-PRODUCING AND EGGLAYING ANIMALS BY FEEDING THE AFOREMENTIONED COMPOUND IN COMBINATION WITH NUTRIENT FEEDS.

United States Patent Oflice Patented Jan. 15, 1974 3,786,149 ANIMAL FEED FOR OBTAINING INCREASED PRODUCTION IN ANIMALS Robert J. Collins, Portage, Mich., assignor to The Upjohn Company, Kalamazoo, Mich. No Drawing. Filed Aug. 9, 1971, Ser. No. 170,329 Int. Cl. A61k 27/00 US. Cl. 424-269 6 Claims Formula 1 wherein R R and R are selected from the group consisting of hydrogen, alkyl of l to 3 carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino and dialkylamino, in which the carbon chain moieties are of l to 3 carbon atoms, inclusive, and wherein R and R are selected from the group consisting of hydrogen and alkyl as defined above and including the pharmacologically acceptable acid addition salts and N-S oxide in combination with a nutrient feed. A process for obtaining increased productivity in meat-producing, milk-producing and egg laying animals by feeding the aforementioned compound in combination with nutrient feeds.

CROSS REFERENCE TO RELATED APPLICATIONS This application is related to copending United States application Ser. No. 852,112, filed Aug. 21, 1969, which discloses compounds of the Formula 1 and methods for their preparation. The aforementioned application issued as Belgian Pat. No. 755,139 on Feb. 22, 1971.

BRIEF SUMMARY OF THE INVENTION Broadly the present invention encompasses a nutritionally adequate animal feed having dispersed therein a compound of the Formula 1 in sufiicient concentration to provide increasing productivity and feed efliciencies in healthy meat-producing, milk-producing or egg-laying animals. The invention also includes the process of feeding the composition to meat-producing, milk-producing or egg-laying animals.

DETAILED DESCRIPTION It has been found in recent years that meat-producing animals will gain more weight and gain it faster when various classes of compounds such as vitamins, minerals, estrogens, antibiotics, and tranquilizers are added to the diet. Although the presently available compounds are useful, new materials are still being sought that would produce weight gains more rapidly, to a greater extent, more efficiently with respect to feed intake at a lower cost and without undesirable side effects.

It is now possible by use of the present invention to obtain unexpected results in the feeding of meatproducing, milk-producing, or egg-laying animals; that is to say, an increased rate of weight gain, an increased amount of weight gain, an increase in milk production, or increased rate of egg laying, as well as increased feed efiiciency, can be obtained by the addition of minute quantities of a compound of the Formula 1 to the animals usual nutrient feed.

Compounds of the Formula 1 can be prepared by methods disclosed in United States application Ser. No. 852,112, filed Aug. 21, 1969 and Belgian Pat. No. 755,139, issued February 22, 1971.

Unless otherwise specified, all percentages are given on a weight-to-weight basis. The pound (1b.) weights given are avoirdupois units.

Feeding of the compositions of the present invention can commence for birds shortly after hatching and in the case of mammals, during the creep-feeding period of suckling animals when they are starting on solid food and, of course, after weaning. Feeding of the compositions is continued throughout the growing period, lactation period, or egg-laying period.

The total concentration of the compound of the Formula 1 in the feed composition is determined with regard to the species of animal, age, weight, and average amount of feed consumed daily. Preferably the compound of the Formula 1 is employed in the finished feed that will supply the animal with a daily intake of from about 0.003 mg. to about 50.0 mg. per head per day.

The following table illustrates the range of compound of Formula 1 in milligrams daily dose per head per day for representative animals.

The foregoing dosage can generally be accomplished by providing from about 25 mg. to about 2500 mg. of a compound of the Formula 1 per ton of finished feed.

Advantageously a compound of the Formula 1 is supplied in the form of a liquid or solid premix wherein the concentration is -2000 times greater than the desired final concentration of the feed. For example, the compound of Formula 1 can be dissolved or suspended in a fluid vehicle such as corn oil, cottonseed oil, molasses, distillers solubles and the like to prepare a fluid premix. Alternatively, a solid premix can be prepared by mixing a compound of the Formula 1 with an edible solid diluent such as sucrose, lactose, starch, corn mealjfiour, calcium carbonate, soybean meal and the like.

EXAMPLE 1 A diet for fattening lambs is prepared from the following types and amounts of ingredients:

Percent Ground ear corn 82.05 Alfalfa meal 10.0 Soybean oil meal 44% 7.0 Ground limestone 0.3

Salt 0.6 Trace mineral mixture- 0.05

1 Contains the following percent of minerals Mn i12; Co, 0.08 Fe, 5.0; Cu, 0.4; I. 0.24; Zn, 0.7.

The above feed is mixed, pelleted and offered to fattening lambs free-choice in conjunction with hay'.' F

To 999 parts of the preceding feed is addedl part of a premix composition prepared'by mixing 0.14 gmiof 8- T6999 parts of the preceding feed is added l part f a premix composition prepared by mixing 0.3 gm. of 8- 7 chloro 2,4 4 dihydro-2-methyl-6-phenyl lH-s-triaiolochloro 2,4 dihydro-Z-methyl-6-phenyl lH-s-triazolo- [4,3-a][1,4]benzodiazepin-1-one hydrochloride with sufficient corn meal to make one pound.

The feeding composition so prepared supplies 0.l4 mg. of 8-chloro 2,4 dihydro-2-methyl 6-phenyl-1H s-triazolo[4,3-a][1,4]benzodiazepin-1-one hydrochloride p'er pound or 0.31 part per million.

The foregoing composition is usefully fed to lambs for increased rate of weight gain and improved utilization of feed.

EXAMPLE 2 A chicken feed for broilers is prepared from the following types and amounts of ingredients:

{-4,3-a][l,4]benzodiazepin-1-one hydrochloride with suf- Percent Yellow corn meal 4- 67.35 Soybean oil meal 24.00 Menhaden fish meal 6.00 Steamed bone meal 1.00 Ground limestone 1.00

Iodized salt .34 25% Choline chloride .13 Vitamin B supplement (6 mg./lb.) .10 Manganese sulfate =.02 Supplemental vitamin mix 1 .06

1 Consisting of 16.0 gm. vitamin A supplement 10 iinits/ mg.) 3.6 gm. vitamin D3 supplement (15,000 units/gin.) 7.1 gm. riboflavin supplement (1 gm. riboflavin per"ounce) 500 mg. P1110111. I I v To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing; 0.2 gm. 8- chloro 2,4 dihydro-2-methyl-6-phenyl-lI-I-s-triazolo- [4,3-a][1,4]benzodiazepin-1-one hydrochloride with sufficient soybean mill feed to make 1 pound.

The feeding composition so prepared supplies 0.2 mg.

of 8-chloro 2,4 dihydro-2-methyl-6:phenyl:lH-s-triazolo[4,3-a][l,4]benzodiazepin 1 hydrochloride per pound, or about 0.44 part per million. v

The foregoing composition is usefully fed to chickens for increased rate of weight gain and improved utiliza tion of feed. Similarly the composition-can ;be fed-*to turkeys, ducks and geese.

EXAMPLE 3 A fattening feed for 800 pound yearling cattleis prepared from the following types and amounts of ingredients:

" Percent 39.75

Ground ear corn Soybean oil meal, 44% 9.0 Ground limestone I 07 Salt H ;o.5 Trace mineral mixture 1 0.05

Contains the following percent of minerals Mn 12 Co, 0.08; Fe, 5.0; Cu, 0.4;1, 0.24;Zn, 0.7. g

[4,3-a][l,4]benzodiazepin-l-one hydrochloride with sufficient wheat flour to make 1 pound.

The feeding composition so prepared supplies 0.3 mg. of 8-chloro 2,4 dihydro-2-methyl-6-phenyl-lH-s-triazolo[4,3-a][l,4]benzodiazepin-1-one hydrochloride per pound, or about 0.66 part per million.

Cattle are to receive the foregoing feed ad libitum together with 5 lb. of hay per head per day and when so fed have an increasedrate of weight gain and improved utilization of feed.v

' *EXAMPLE 4 A swine diet for growing hogs of 40 to pounds body weight is prepared from the following types d amoums of ingredients:

1 Contains the following percent of minerals: Mn, 12; Co, 0.08 Fe, 5.0; Cu, 0.4; I, 0.24; Zn, 0.7.

Contains, 300 USP units Ds/gm. and 1500 I.U.A./gm.

Contains per 111.: riboflavin, 2000 mg.; calcium pantotlieggge, 4000 mg.; niacin, 9000 mg.; and choline chloride 4 Contains 6 mg. vitamin B12 per lb.

To 999 parts of the preceding feed is added 1 part of a premix composition preparedby mixing 0.15 gm. of 8-chloro 2,4 dihydro-Z-methyl-6-phenyl-lH-s-triazoloficient ground limestone to make one pound.

The feeding composition so prepared supplies 0.15 mg. of 8-chloro-2,4"-dihydro 2 methyl-'o-phenyl-1H-s-triaz olo[4,3-a][1,4]benzodiazepin-1-one hydrochloride per pound. or about 0133 part per million.

The foregoing composition 'is usefully fed tdhog for increased rate of weight gain and improved utilization of feed.

' "-Following" the procedure of the preceding Examples 1 to 4, inclusive, animal feeds are similarly prepared substituting-equimolar'amounts of:

EXAMPLE 5 8-chloro-2,4-dihydro-o-phenyllH-s-triazolo [4,3-a] 1,4]-

benzodiazepin-l-one;

' 7-chloro-2,4-dihydro-6-phenyl-lH-s-triazolo4.3-a] 1,4

'benzodiazepin-l-one; a

benzodiazepin-l-one; I 1O-trifluoromethyl-Z,4-dihydro-6-(p-propionylamino- H phenyl) -lH-s-triazolo [4,3-a] [1,4] benzodiazepin l-one; 9-cyano-2,4-dihydro-6- (p-trifiuoromethylphenyl)-1H-striazolo'[4,3-a] [1,4]benzodiazepin-1-one; 9-propoxy-8-bromo 2,4-dihydro-6-(m-methylsiilfinylphen yl)'-lH s-triazolo[4,3-a] [1,4]be'nzodiapein-1-one;

8,9-dicyano-2,4-dihydro-6- (p-methylsulfonylphenyD-1H- s-triazolo[4,3-'a] [1,4]benzodiazepin--1-one;

1O-acetylaminO-2,4-dihydro-6 -(p-cyanophenyl)-1H-striazolo[4,3-a] [1,4] benzodiazepin-lone; i v

7,9-diethyyl-2,4-dihydro-6- (m-ethylphenyl -1H-striazolo [4,3-a] 1, 4]benzodiazepin-l-one; 2,4-dihydro-6-phenyllH-s-triazolo [4,3-a] [1,4] benzodiazepin-l-one; 8-chloro-2,4-dihydro-2-ethyl-6-phenyl-1H-s-triazolo- [4,3-a] [1,4] benzodiazepinl-one; 8-bromo-2,4-dihydro-2-propyl-d-phenyl-lH-s-triazolo- [-4,3-a] [1,4] benzodiazepinl-one; -trifiuoromethyl-Z,4-dihydro-2-isopropyl-6- (p-propionylaminophenyD-1H-s-triazo1o[4,3-a] 1,4] benzodiazepinl-one; 2,4,7,9-tetramethyl-2,4-dihydro-6- (o-chlorophenyl) -1H-striazolo [4,3-a] [1,4]benzodiazepin-1-one; 8,9-dicyano-Z,4-dihydro-2-ethyl-6- p-methylsulfonylphenyl)-1H-s-triazolo[4,3-a] [1,4] benzodiazepinl-one; 7-chloro-2,4-dihydro-6- m-bromophenyl) -1H-s-triazolo- [4,3-a] [1,4]benzodiazepin-1-one; 8-methyl-2,4-dihydro-6-pheny1-1H-s-triazolo[4,3-a] [1,4]

benzodiazepin-l-one; 8-nitro-2,4-dihydro-6-phenyl-1H-s-triazolo[4,3-a] [1,4]

benzodiazepin-l-one; 8-fluoro-2,4-dihydro-6-phenyl-1H-s-triazolo[4,3-a] [1,4]

benzodiazepin-l-one; 8-trifiuoromethyl-2,4-dihydro-6-phenyllH-s-triazolo- [4,3-a] [1,4] benzodiazepin-l-one; 8-cyano-2,4-dihydro-6-phenyllH-s-triazolo 4,3-a] 1,4]

benzodiazepin-1one; 8-chlo ro-2,4-dihydro'6- (o-chlorophenyl) -1H-s-triazolo- [4,3-a][1,4]benzodiazepin-l-one; 7- ethylthio-2,4-dihydro-6- (o-bromophenyl) lH-s-triazolo- [4,3-a] [1,4[benzodiazepin-1-one; 6,8-dichloro-2,4-dihydro-6- (o-fiuorophenyl) -1H-s-triazolo [4,3-a] [1,4] benzodiazepinl-one; 9-nitro-2,4-dihydro-6- (o-chlorophenyl) -1H-s-triazolo- [4,3-a] [1,4] benzodiazepin-l-one; 8-bromo-2,4-dihydro-6- (o-bromophenyl) -1H-s-triazolo- [4,3-a] [l,4]benzodiazepin-1-one; 8-methylsulfinyl-2,4-dihydro-6- (o-fluorophenyl l H-striazolo [4,3-a] [1,4]benzodiazepin-1-one; 10-propylsulfonyl-2,4-dihydro-8-methyl-6-phenyl- 1 H-striazolo [4,3-a] [1,4]benzodiazepin-1one; 8-dimethylamino-2,4-dihydro-6-phenyllH-s-triazolo- [4,3-a] [l,4]benzodiazepin-1-one; 8,9-dicyano-2,4-dihydro-6- (p-methylsulfonylphenyl) -1H- s-triazolo [4,3-a] [1,4]benzodiazepinl-one;

for the 8-chloro-2,4-dihydro-2-methyl-6-phenyl-lH-s-triazol0[4,3-a][1,4]benZodiazepin-l-one hydrochloride of the examples.

I claim:

ll. A process for obtaining increased meat, milk or egglaying production in an animal comprising the feeding of from about 0.006 to about 50 mg./day of a compound selected from the group consisting of 2,4-dihydro-6-phenyl-lH-s-triazolo[4,3-a] [l,4]benzodiazepin 1 one of the formula:

wherein R R and R are selected from the group consisting of hydrogen, alkyl of l to 3 carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, akanoylamino and dialkylamino, in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive, and wherein R and R are selected from the group consisting of hydrogen and alkyl as defined above and including pharmacologically acceptable acid addition salts and N-S oxides in combination with the nutrient feed to a meat-producing, milk-producing or egg-laying animal in need of said increased production.

2. A process of claim 1 wherein the member selected is in a concentration of from 25 mg. to 2500 mg. per pound of nutrient carrier in the form of a premix.

3. A process of claim 1 when the member selected is in the concentration from 50 mg. to 5000 mg. per ton of feed.

4. A process of claim 1 wherein the compound is 8- chloro 2,4 dihydro-Z-methyl-6-phenyl-lH-s-triazolo- [4,3-a] [1,4]benzodiazepin-1-one hydrochloride.

5. A process of claim 2 wherein the compound is 8- chloro 2,4 dihydro-2-methyl-6-phenyl-lH-s-triazolo- [4,3-a] [1,4]benzodiazepin-1-one hydrochloride.

:6. A process of claim 3 wherein the compound is 8- chloro 2,4 dihydro-2-rnethyl-6-phenyl-lH-s-triazolo- [4,3-a] [1,4]benzodiazepin-1-one hydrochloride.

References Cited UNITED STATES PATENTS 3,646,055 2/1972 Hester 424-269 JEROME D. GOLDBERG, Primary Examiner 

